General Effects of α Blockers

GENERAL EFFECTS OF α BLOCKERS

·        Blockade of vasoconstrictor α₁ (also α₂) receptors reduces peripheral resistance and causes pooling of blood in capacitance vessels → venous return and cardiac output are reduced → fall in BP. Postural reflex is interfered with → marked hypotension occurs on standing → dizziness and syncope. Hypovolemia accentuates the hypotension. The α blockers abolish the pressor action of Adr, which then produces only fall in BP due to β_ mediated vasodilatation—vasomotor reversal of Dale. Pressor and other actions of selective α agonists (NA, phenylephrine) are suppressed.

·        Reflex tachycardia occurs due to fall in mean arterial pressure and increased release of NA due to blockade of presynaptic α₂ receptors.

·        Nasal stuffiness and miosis result from blockade of α receptors in nasal blood vessels and in radial muscles of iris respectively.

·        Intestinal motility is increased due to partial inhibition of relaxant sympathetic influences— diarrhoea may occur.

·        Hypotension produced by α blockers can reduce renal blood flow → g.f.r. is reduced and more complete reabsorption of Na+ and water occurs in the tubules → Na+ retention and increase in blood volume. This is accentuated by reflex increase in renin release mediated through β₁ receptors.

·        Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of α₁ receptors (mostly of the α_1A subtype) → urine flow in patients with benign hypertrophy of prostate (BHP) is improved.

·        Contractions of vas deferens and related organs which result in ejaculation are coordinated through α receptors—α blockers can inhibit ejaculation; this may manifest as impotence.

·        The α blockers have no effect on adrenergically induced cardiac stimulation, bronchodilatation, vasodilatation and most of the metabolic changes, because these are mediated predominantly through β receptors.

Apart from these common effects, most of which manifest as side effects, many α blockers have some additional actions. Their pharmacological profile is also governed by their central effects and by the relative activity on α₁ and α₂ receptor subtypes. Only the distinctive features of different α blockers are described below.

Phenoxybenzamine It cyclizes spontaneously in the body giving rise to a highly reactive ethyleniminium intermediate which reacts with adrenoceptors and other biomolecules by forming strong covalent bonds. The α blockade develops gradually (even after i.v. injection) and lasts for 3–4 days.

In isolated preparations of vascular smooth muscle, low concentrations cause DRC of NA to shift to right without suppression of maxima

(till spare receptors are available); higher concentrations progressively flatten the DRC and nonequilibrium antagonism is manifested. Increased release of NA from sympathetic nerves (due to α₂ blockade) occurs and reflex tachycardia is prominent in intact animals. Partial blockade of 5HT, histaminergic and cholinergic receptors, but not β adrenergic receptors, can be demonstrated at higher doses.

The fall in BP caused by phenoxybenzamine is mainly postural because venodilatation is more prominent than arteriolar dilatation. In recumbent subjects cardiac output and blood flow to many organs are increased due to reduction in peripheral resistance and increased venous return. It tends to shift blood from pulmonary to systemic circuit because of differential action on the two vascular beds. It also tends to shift fluid from extravascular to vascular compartment. Phenoxybenzamine is lipid soluble, penetrates brain and can produce CNS stimulation, nausea and vomiting on rapid i.v. injection. However, oral doses produce depression, tiredness and lethargy. Major side effects are postural hypotension, palpitation, nasal blockage, miosis, inhibition of ejaculation.